Journal Watch - March 2012

JAMA 28 Mar 2012 Vol 307

1257 Medical conferences exist to affirm everything that hinders the progress of medicine as a compassionate and honest enterprise. They are a showcase for authority figures, pharma-funded research, half-completed work in the form of abstracts and late-breaking sessions; they use up prodigious amounts of money and carbon fuels; they reward high-tech flashiness and set no value on basic care and joined-up thinking: they reinforce a career structure and a social hierarchy in medicine which undermines the whole concept of patient-centredness. I'm glad to see all these feelings shared by John Ioannidis in this Viewpoint piece. John is a famous iconoclast who wrote the classic 2005 PLoS Medicine paper, Why Most Published Research Findings Are False. Here he proposes that nobody with any ties to industry over the preceding 3 years should be allowed to organize a conference. Also, that in order to ascertain the educational benefit of conferences, the next one should be randomized.
http://jama.ama-assn.org/content/307/12/1257.extract

1273 Look into your hearts, my brothers and sisters! How few of you are saved from the perdition of cardiovascular risk! Just 1.2% of Americans can count themselves truly upright, by not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet. The rest are mired in sin - by genetic predestination or moral turpitude; and the world grows ever less righteous. According to the John Calvin of epidemiology, the late Geoffrey Rose, cardiovascular disease should have doubled since 1992, when he published his book The Strategy of Preventive Medicine. Instead it has halved. How depressing it must be for the Calvinists when so many sinners fail to die.
http://jama.ama-assn.org/content/307/12/1273.abstract

1307 One reason that so many sinners survive is the widespread use of statins in high-risk patients. Wistful for the enormous profits that these drugs brought in during the last two decades, pharma companies continue to search for a lipid-lowering drug which will add to the effect of HMG co-reductase inhibition. So what is the lipid subfraction that most predicts risk in people taking statins? Here's a painstaking individual patient data meta-analysis showing that it is not low-density lipoprotein cholesterol alone, nor apolipoprotein B, but the totality of non-high-density lipoprotein cholesterol. Lower this, and you may have the next lipid-lowering blockbuster; or you may have nothing; or you may kill people.
http://jama.ama-assn.org/content/307/12/1302.abstract

NEJM 29 Mar 2012 Vol 366

1181, 1190 "Few adverse effects were observed, and few patients withdrew from the trials. Nevertheless, a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17. Future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed." So says the sage editorialist, who also explains the interleukin 17 system and many other arcane pathways that may be involved in psoriasis. Nevertheless, the NEJM has thought fit to publish these trials, no doubt because we would all like to see better treatments for psoriasis, and this approach shows promise. It could also be that these papers may help Amgen and Eli Lilly get FDA approval for brodalumab and ixekizumab, respectively. As I've said before, the companies may find the need to buy many reprints of these papers from the NEJM: this has happened before, and is part of the normal business structure of medical publishing, hidden behind a wall of commercial secrecy. Whether this results in the best selection of studies, or improvement of clinical practice, is for you to judge.
http://www.nejm.org/doi/full/10.1056/NEJMoa1109017
http://www.nejm.org/doi/full/10.1056/NEJMoa1109997
http://www.nejm.org/doi/full/10.1056/NEJMe1201071

1209 I have written a lot about patient-important outcomes in type 2 diabetes, but one that we can easily overlook is mobility. In obese people with T2DM, loss of mobility leads to a downward spiral of diminished energy loss, muscle atrophy and increase in adiposity: worsening glycaemic control then leads to all the problems of insulin therapy in people who cannot exercise and are insulin resistant. We have all seen this happen to our patients, and it is likely to become a commoner sight throughout the world unless we can find an effective intensive lifestyle intervention - one that can be applied to millions of individuals. The Look AHEAD trial enrolled more than 5,000 patients and achieved a 40% reduction in loss of mobility over 4 years in its intensive intervention arm. This could be of generalizable importance. Methodology buffs will also be impressed with the sophistication of the analysis: "We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline." A worthwhile paper.
http://www.nejm.org/doi/full/10.1056/NEJMoa1110294

1227 Blindness is certainly a patient-important outcome in diabetes, and here is an excellent and optimistic review of diabetic retinopathy. Optimistic because the incidence of diabetic retinopathy is falling, and there are effective new treatments based on vascular endothelial growth factor (VEGF) inhibition. It is worth mentioning in passing that despite popular myth, glycaemic control has only a minor effect on eye disease in T2DM. The role of VEGF in the process, however, is crucial. Intravitreal glucocorticoids and VEGF inhibitors are playing an increasing role in the treatment of established eye disease. Intriguingly, inhibitors of the renin-angiotensin system have been found to confer specific protection against retinopathy in type 1 diabetes, and fenofibrate protects against non-proliferative retinopathy in type 2. What, a use for fenofibrate at last?
http://www.nejm.org/doi/full/10.1056/NEJMra1005073

Lancet 31 Mar 2012 Vol 379

1199 Hard on the heels of the BMJ's exposure of the harms of metal-on-metal hip replacements comes this damning analysis of the National Joint Registry of England and Wales. There has been a tremendous vogue for these devices, especially in young patients. It was thought that the larger the head, the better. Now the evidence has belatedly caught up with orthopaedic fashion, and the truth is devastating. Metal-on-metal devices should never have been licensed, and the bigger the head, the sooner they fail. The opposite is true of ceramic devices. Metal on polythene devices also work well. This is a scandal of regulation which could probably still happen - for all we know, it is happening as we speak, in some other area of the lucrative, virtually free-for-all market of medical devices.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960353-5/abstract

1205 The Higher Calvinism of cardiology is a terrifying religious system of predestination by genomics. Someone needs to write a satirical novel about it, like James Hogg's grim tale of Scottish Calvinism gone mad in Private Memoirs and Confessions of a Justified Sinner (1824). The latest focus of genomic theology is interleukin-6 receptor (IL6R) signalling, one of the many ways by which the wrathful gene-god dooms the unworthy to suffer cardiovascular disease. Never mind that we know many other important ways, and that this one is just an aspect of general inflammation. The Church of Genomics demands that we must not pit our humble understanding against a list of authors and investigators which covers two pages of small print. The entire priesthood proclaim that by analysing 82 studies, they can affirm that "large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease." Aye, consistent with. What more can the faithful believer require?
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961931-4/abstract

1214 The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium is a much smaller group - a mere 100 or so - but by combining the results of 40 studies in 133,449 individuals, it too concludes that "IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials." Well, hold on. Most of us accept that inflammation plays a role in the ulceration of arterial plaque, and hence cardiovascular events. IL6R signalling is part of that process. It is also part of our inflammatory defence system, and perhaps a host of other things we don't fully understand. In the editorial, we learn that large-scale trials of decidedly worrying agents such as methotrexate and canakinumab are already under way for vascular protection based on interleukin pathways. I just hope these guys know what they are doing. It will take more than a few "seems" and "consistent withs" to make me believe this mechanistic logic, however hard won.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960110-X/abstract

1256 Have you run out of things to worry about? Fancy mongering a new disease? Try hyposelenaemia. The basis for selenium supplementation, according to this review, is that "low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline." Alas, I am ignorant of my selenium status. I don't even know my credit rating or my IQ. And I certainly shan't rush to buy selenium from a "health" shop or online, because "supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes." So why are these supplements on open sale? Shouldn't we insist on a plasma selenium level first? Tell me, has anyone ever put "plasma Se" on a blood form?
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961452-9/abstract

BMJ 31 Mar 2012 Vol 344

Promoting exercise in sedentary patients is undoubtedly a worthwhile endeavour, but that does not mean we know how to do it effectively. A bit of exhortation now and again is unlikely to work, so the temptation is to refer patients elsewhere, and I have certainly written out lots of exercise prescriptions to local gyms. Unfortunately we don't really know if this tactic works either. This systematic review from the Cambridge primary care department reaches a rather downbeat conclusion.
http://www.bmj.com/content/344/bmj.e1389

Florence Nightingale in the 1860s believed that hospitals were "an intermediate form of life", dangerous to patients and soon to be superseded by teams of nurses who would look after sick people in their own homes. She really believed in the transfer of services to primary care, unlike most politicians who use it as a cynical excuse for disinvestment in hospitals. Hospitals in most places remain dangerous, inhumane environments: but absolutely irreplaceable, especially in the developing world. This survey of 26 hospitals from countries such as Egypt, Jordan, Kenya, Morocco, Tunisia, Sudan, South Africa and Yemen shows a high rate of potentially preventable patient harm. Mind you, so do many surveys of hospitals in rich countries. A study a couple of weeks ago showed that about half the hospital nurses in Europe would run away and do something else if they could. There is something about the culture of hospitals which needs hard work to repair.
http://www.bmj.com/content/344/bmj.e832

Plant of the Week: Prunus avium

The wild cherry can be a pretty huge tree, growing to 25m high and across, and there is no finer spring sight than a fully grown one in flower. Its other names are supposedly the bird cherry, gean, or mazzard; but I have yet to hear an English villager exclaim "Why yon's a glorious gean!" or "What a mighty mazzard that be!", though if I looked hard enough in the works of Thomas Hardy I might find such words.

It is the plant referred to in the lines of E A Housman, recited by every schoolchild of my period:

LOVELIEST of trees, the cherry now
Is hung with bloom along the bough,
And stands about the woodland ride
Wearing white for Eastertide.
Now, of my threescore years and ten,
Twenty will not come again,
And take from seventy springs a score,
It only leaves me fifty more.
And since to look at things in bloom
Fifty springs are little room,
About the woodlands I will go
To see the cherry hung with snow.

With only eight years left to go by Housman's reckoning, I'd love to wander out into the woods of New England to admire the local cherry species - which are abundant, though smaller and less floriferous. But to save me time and effort, someone has planted the great European gean on my daily walk to work. It must be about 100 years old and it is entirely hung with snowy bloom this Eastertide. Loveliest of trees.


JAMA 21 Mar 2012 Vol 307

1161 When in Japan, do not attempt to drop down dead. In 800 fire stations around the Islands of the Sun, teams of emergency medical service personnel stand ready to rush out and perform resuscitation for out-of-hospital cardiac arrest, which cannot be discontinued until an ambulance arrives and you are taken to hospital, barely alive or truly dead. This non-randomized study of Japanese CPR shows that if the emergency team used epinephrine (adrenalin), your chance of having spontaneous circulation when you arrived in hospital would be 18.5%, and if they did not, it would be 5.7%. On the other hand, your chance of being alive at one month without major neurological impairment would be 1.4% if you had been given epinephrine, and 2.2% if you had not. So I think we can conclude that epinephrine should not be given during CPR. Next we need to find out whether out-of-hospital CPR should be given at all, since there is no firm evidence one way or the other.
http://jama.ama-assn.org/content/307/11/1161.abstract

1185 A lot of elderly people get deaf. Hearing aids can be useful, but this does not show up well in overall assessments of quality of life. Many deaf elderly people have other health problems which require a multidisciplinary team approach. I thought I'd tell you this in case you don't have time to read this Clinician's Corner piece, and didn't already know.
http://jama.ama-assn.org/content/307/11/1185.abstract

NEJM 22 Mar 2012 Vol 366

1079 We've all been hoping for early wins in cancer genomics, but they are tantalizingly slow to arrive. With a few dazzling exceptions, cancer therapeutics moves through a painful grind of incremental progress. Here the investigators performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had acute myeloid leukaemia. They were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin, and the prognostic findings were compared with an independent set of 104 patients. Several gene loci were identified that predict response to this kind of treatment. And so the grind goes on: all credit to those who undertake it.
http://www.nejm.org/doi/full/10.1056/NEJMoa1112304

1090 And here's a study of the Clonal Architecture of Secondary Acute Myeloid Leukaemia: more evidence that in cancer biology, complexity rules. Secondary AML is the kind that arises from myelodysplasia, and I can't do better than quote from the Abstract: "Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones." In the new world of genomics, don't look for simple mechanistic targets: look for fractal patterns, Fibonacci sequences, emergent properties, and all the other beautiful and dangerous things that make the crooked timber of humanity so interesting, and so hard to predict.
http://www.nejm.org/doi/full/10.1056/NEJMoa1106968

1099 The first trials of thrombolysis for stroke were carried out twenty years ago, but treatment with alteplase still occupies a marginal place in the everyday management of acute ischaemic stroke, despite efforts to encourage its use within the small window of benefit. But what if there were a thrombolytic agent that was nearly twice as good? This publicly funded Antipodean study compared two doses of tenecteplase with a standard dose of alteplase with just 25 carefully selected patients in each group. The higher dose of tenecteplase definitely produced the best results (72% v 40% disability-free at 90 days), but we need a bigger trial.
http://www.nejm.org/doi/full/10.1056/NEJMoa1109842

1108 When monoclonal antibodies were first produced, nearly 40 years ago, we were told to expect lots of magic bullets for a wide array of hitherto untreatable diseases. My whole working lifetime has passed by in those decades, and only a handful of my patients ever received treatment with a monoclonal antibody, usually with broad and unpredictable effects. High low-density lipoprotein cholesterol is a common biochemical finding, whether due to heritable causes or not. It is certainly associated with worse cardiovascular outcomes. So what might happen if we give people with raised LDL-C a monoclonal antibody to the enzyme which promotes LDL-C production? This enzyme is called proprotein convertase subtilisin/kexin 9 [PCSK9], but I don't expect you to remember that. And the monoclonal antibody to PCSK9 is designated as REGN727/SAR236553 (REGN727), and I don't expect you to remember that either. In fact I don't expect you to remember anything about this study at all, except that the stuff reduced LDL-C levels in a few healthy volunteers and a few subjects with familial and non-familial hypercholesterolaemia, and did them no immediate harm. Or good. Now just keep this in the back of your mind, for the ten years of phase 2 and 3 trials that it will need to see if it's safe and if it reduces events.
http://www.nejm.org/doi/full/10.1056/NEJMoa1105803

Lancet 24 Mar 2012 Vol 379

1103 According to themost recent post-mortem studies, the chances of a man of my age having localized prostate cancer are about 50-50. Whether it is detected or not depends on how many sharp instruments are repeatedly used to sample tissue via my rectum, which is why I am staying firmly seated. If I were truly worried, I think I would rather castrate myself, like some Early Father of the Church. Or I could take dutasteride, thus contributing to the profits of GlaxoSmithKline, who funded this trial and did most of the writing up. At three years the only difference I might notice would be an increased risk of sexual dysfunction. All other discernible outcomes would be much the same, but if I allowed the needle back up my rectum, less progression of my low-risk "cancer" might be found (hazard ratio 0.62, 95% CI 0.43-0.89). I am staying firmly seated, and I shan't be asking my GP for dutasteride. Maybe just for lidocaine, in case I take the castration route.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961619-X/abstract

1112 The nearest place to heaven on earth is New Zealand, but there is a serpent in this paradise (not literally: there are no snakes in New Zealand). There is guilt and inequality, even in this haven of non-violence and social progress. The white majority, descended mostly from British colonists of the nineteenth century, feel a legacy of bad conscience towards the Maori population, descended mainly from Polynesian colonists of the thirteenth century. Legend has it that all Maori people take their ancestry from just 13 individuals who survived the first journey in a boat that had lost its way. When British settlement began, they were deprived of much of their land by the Treaty of Waitangi, and barely survived extinction from European infectious diseases and economic domination over the next century. Born from fishers and hunter-gatherers, they have a "thrifty genotype" that helped them to get through times of famine, and their legends extol the low glycaemic diet of fish and moa meat that they kept to until white settlers arrived. This came just after the final extinction of the moa, a large flightless bird whose culinary qualities will remain legendary until someone manages to recreate it from surviving DNA. Clearly this is an urgent challenge for scientific gastronomy, but I digress. The point is that the Maori in New Zealand today, are showing increasing levels of hospital admission for acute infectious disease. Social deprivation and poor access to services play a part, and likewise their very high levels of obesity and hyperglycaemia, legacies of their ancestry in an age of abundant carbohydrates.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961780-7/abstract

1142 "Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease." I would suggest that few things are less urgent than such trials on people with accidentally discovered borderline levels of TSH. But you may like to read this review and make up your own mind.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960276-6/abstract

1155 Thyrotoxicosis on the other hand is definitely important, and it was the first diagnosis I ever made - at the age of 15 on the mother of a friend, who had a swollen neck and bulging eyes and shaky hands, like a description I had read in a chemistry textbook. She responded to surgery and carbimazole, and maybe radio-iodine. I don't think there have been many advances in the 46 years since then, apart from beta-blockers for temporary symptom control: in fact this excellent review of the condition admits as much in its final paragraph.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960782-4/abstract

BMJ 24 Mar 2012 Vol 344

I searched in vain for original research to inform your practice or your thinking in this week's BMJ, but there is a gem of a piece by Lisa Schwartz and Steven Woloshin on the website, with the promise of more Not So Stories to come:

First an apology and retraction. Two weeks ago, I praised an MRC-funded study which claimed to show a clinically significant from continued use of donepezil or memantine in patients with moderate to advanced Alzheimer's disease. Margaret McCartney pulled me up on this: although the study was conducted by good investigators and had no pharma funding, it still grossly overstated the significance and reliability of its results. These were tiny differences which would never be noticed by the patients (by definition) and scarcely by their carers, since the disease progresses inexorably whatever you do. If I had to fix a budget for my locality, I would rule out the use of these drugs in this population. And as soon as I return to the UK, I shall buy Margaret's new book, The Patient Paradox: why sexed-up medicine is bad for your health.

But now to Steven and Lisa's Not So Story. Re-enter donepezil, now off-patent at 10mg, but still patentable at 23mg for three years' worth of lucrative sales, if only the U.S. Food and Drug Administration could be persuaded. There is actually a head-on study comparing the 10mg with the 23mg dose and showing no benefit and more adverse effects. So how did Eisai, the drug's manufacturer, persuade the FDA to allow this formulation to be marketed? By the usual box of tricks - direct-to-public marketing, grossly misleading advertising to doctors, blatantly repeated on the labelling: all of which caused enough demand for the FDA to give way. Quis custodiet ipsos custodes?
http://www.bmj.com/content/344/bmj.e1086

The other good thing on the website is an editorial called "Putting Patients First". A tired old cliché? Maybe: but also the responsibility we carry now more than ever before, and the one thing that will save the NHS from the destruction willed upon it by politicians of every flavour. And this is a superbly written piece, arguing that everything we do should begin and end with the patient experience. Perhaps that is why it is behind the BMJ paywall, so that patients can't read it and get ideas above their station.
http://www.bmj.com/content/344/bmj.e2006

Ann Intern Med 20 Mar 2012 Vol 156

405 Aha, here is the latest trial of a drug for type 2 diabetes, paid for by its manufacturers. This one is called Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial. Now, what do you as a prescribing clinician need to know about the "long-term efficacy" of a drug which you will be discussing with your patient who has type 2 diabetes? Well, obviously it would be nice to know it if reduces the likelihood of cardiovascular events, blindness, renal failure etc. over a period of say ten years. Efficacy would imply that it is cost-effective compared to other treatment options. And what do we have here? A 24-week study showing that it reduces HbA1c and weight in some patients taking large doses of insulin. "However, this study could not evaluate long-term effectiveness and safety concerns that have hindered approval of this drug by the U.S. Food and Drug Administration" mourns the Annals summarist. Ah well, perhaps the FDA has its uses after all.
http://www.annals.org/content/156/6/405.abstract

Plant of the Week: Magnolia cylindrica

The magnolias of New England are suddenly all out at once, as their flower buds have been irradiated by sunshine at temperatures of 25 degrees or more. The overwhelming favourites here as everywhere are M kobus var stellata and M x soulangeana. They are lovely and fragrant and always welcome at this time of year, but just a weeny bit boring.

The magnolia I always most desired, and possessed briefly, is the one known as "cylindrica (of gardens)". The "of gardens" is a sniffy botanical term implying that this may not be exactly the plant first described by its discoverer - in this case no less than the greatest of plant hunters, E H Wilson of Chipping Norton. Though this is a beautiful plant both in flower and in seed, it is actually very rare in gardens - in fact I have never seen it in one, except in my own, which soon became its graveyard. So do try to find M cylindrica (of gardens), but when you do, prepare a luscious bed of well-rotted dung for it, and keep it away from limy material of any sort. Send me photos of its lovely white flowers with their pink bosses, and it bright red seed pods in autumn. I shall then regard you with gratitude, mixed with faint and friendly resentment.


JAMA 14 Mar 2012 Vol 307

1029 The Viewpoint pieces in JAMA this week are a strange mix of fact and fantasy. The first is a piece about industry payments to physicians and teaching hospitals in the USA. I am currently at Yale University alongside the authors of this piece, one of whom is a good friend. I am observing the US health system at first hand, so I can tell you what is coming to the NHS. You think it's bad enough that private firms are already buying up NHS hospitals and child health services? You ain't seen nothing yet. The whole of the American health system is saturated with the influence of the pharmaceutical and medical devices industry: huge payments are made directly to individuals or institutions to influence purchasing decisions. In the UK, we call this corruption, but only for the time being: look at those lists of payments to our MPs from private health providers published in the Daily Mail, of all places. No wonder our legislators are baffled by all the opposition they are facing from British doctors as they try to open up our antiquated socialist NHS to the healing influences of unbridled capitalism. Come on all you GPs who will be running NHS plc - there is money to be made by everybody! In America there is due to be public listing of all such payments in 2013. I wonder if it will make any difference. It is wonderful how much public disquiet people can handle when they have a few million in the bank.
http://jama.ama-assn.org/content/307/10/1029.extract

1031 The next piece argues that everything will nonetheless be all right in the end, because genomics will come to the rescue. There is a technical fix for everything, and industry is smart enough to find it. Look, the cost of genomic profiling is falling all the time! Soon we will be able to treat fewer people because their DNA will tell us whether the drugs will work or not. And of course we will produce all sorts of better targeted drugs. It's just a shame that they mostly cost $10K per month at present. But all this is bound to change, provided we look to the gleaming towers of lucrative science and ignore the ubiquitous realities of poverty and old age.
http://jama.ama-assn.org/content/307/10/1031.extract

1033 And we must do more to prevent depression. The main reasons given in this paper are little to do with the misery of individuals but the misery that they may spread to others by being so miserable, and their effect on economic productivity. We must be on the look-out for people who do not smile enough, i.e. those with "subsyndromal symptoms": "Methods with proven effectiveness involve educational, psychotherapeutic, pharmacological, lifestyle, and nutritional interventions" The use of booster sessions and Internet technologies should be explored." This sounds like a great idea. Pretty well everyone has pre-depression and if everybody gave each other encouragement, education, a good lifestyle and good nutrition we would all be happier. This used to be called the welfare state. But obviously it's better to trap people in a hopeless cycle of debt and work (or lack of it) and then bring in private counsellors to address their pre-depression issues, and give them serotonin reuptake inhibitors.
http://jama.ama-assn.org/content/307/10/1033.full

1037 Every now and again, Canada is held up as an example of how to provide good health care. In fact, last week JAMA daringly had a Canadian advise the USA on how to set up a better health system. So, does the experience of Canada tell us that we should attempt to provide better care by reducing hospital staffing and costs? Well, actually, it tells us the very opposite. Mortality and readmission rates were lowest in hospitals with the highest costs and levels of spending. Canada works with a system of private providers. So if we want to improve the NHS, we should bring in private competition, and if we want good care we should purchase it from the providers with the highest costs. Or if we want rubbish care, we should buy if from the lowest bidder. This will be the responsibility of all GPs acting on behalf of their patients. You know it makes sense.
http://jama.ama-assn.org/content/307/10/1037.abstract

1072 Does This Patient Have a Severe Upper Gastrointestinal Bleed? My pre-test probability is high. I am an old man taking low dose aspirin, driven to dyspepsia by the thought of the undemocratic destruction of the NHS, seized with griping upper abdominal pain whenever I hear the words "Liberal Democrat". I will spare you a description of my stools. Though this would be vital in the clinical situation, and might save me from a rectal examination in the emergency department. Here is a first-rate contribution to the first-rate Rational Clinical Examination series: "Melena, nasogastric lavage with blood or coffee grounds, or serum urea nitrogen:creatinine ratio of more than 30 increase the likelihood of a UGIB. (NB: Why don't we have this in the UK?)The Blatchford clinical prediction score, which does not require nasogastric lavage, is very efficient for identifying patients who do not require urgent intervention." The Blatchford score was devised in Glasgow (by a GP, amongst others) but the original Lancet paper from 2000 is still behind an Elsevier paywall. But you can get the score on Wikipedia. Everyone should work to make Wikipedia the foremost reliable source of medical information, and to make the Elsevier business model a thing of the past. This won't help to save the NHS, but at least it will help to get knowledge out where it is most needed, i.e. the resource-poor world.
http://jama.ama-assn.org/content/307/10/1072.abstract

NEJM 15 March 2012 Vol 366

981 Here is the screening paradox summed up in a single study. The European Randomized Study of Screening for Prostate Cancer used prostate specific antigen - often called PSA because it has Perfectly Stupid Attributes for a screening test. Nonetheless, in this 11-year follow-up study, the risk of death from prostate cancer was lowered by 21-29%. But all-cause mortality did not differ between groups. Amazingly, I have seen this declared a success for PSA screening in some of the American medical press. Now clearly, if you don't mind what goes on your death certificate, prostate screening is a waste of time. But to inform our advice to patients, let's look at it from the perspective of somebody who had decided they would rather die of anything but prostate cancer. "To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected." So if you had a "cancer" detected by screening, there is a one-in-37 chance that treatment would prevent your death within 11 years. And your odds of dying from anything in that period would be the same.
http://www.nejm.org/doi/full/10.1056/NEJMoa1113135

991 In my last year as a proper GP, I presented two cases from my practice of young women who had suffered cryptogenic stroke and had been found to have patent foramen ovale. OK, foramina ovales. I gathered together myself and a GP partner and a local stroke doctor and some interventional cardiologists from Oxford, and we had a high old time congratulating ourselves on our diagnostic acumen while the receptive audience admired real-patient videos showing the technical wizardry of percutaneous PFO closure. Clearly, we had saved these ladies from the dangers of recurrent stroke by the timely deployment of sophisticated interventions based on impeccable mechanistic insight. But even during the presentation, there was a slight feeling of unease when the evidence base for this presumption was interrogated: PFOs can be found in 25% of the population and there didn't seem to be an adequately powered study to compare device closure of PFOs with medical therapy. Well, now there is, with a follow-up period of two years, and there is no difference in outcomes so far. So while I was trying for one last time to share some of the glamour of sophisticated sexy medicine, perhaps all that these patients needed was what I had tried to provide them with for the whole of my working life - good primary care.
http://www.nejm.org/doi/full/10.1056/NEJMoa1009639

1000 Another week, another study of a new oral treatment for relapsing-remitting multiple sclerosis. This one is called laquinimod, and as far as I can tell it is about the same as all the others - it produces a modest decrease in the rate of relapses and a 4.6% absolute decrease in progressive disability over two years. The study was placebo-controlled and conducted at 139 sites in 24 countries. It was paid for, designed and analysed by Teva Pharmaceutical Industries, and the paper was written with help of an external writing agency. There seems no obvious reason why laquinimod should not now be licensed for use in MS at a cost similar to that of other novel agents, even though we know little about its long-term harms or benefits or how it compares head-on with these other treatments. We demand very little from our licensing agencies before drugs like these can be tested on patient populations. Patients are seldom told they are being used experimentally, doctors have no real means to judge their place in therapy, and meanwhile drug companies can get rich on what they charge for them. Maybe we are all fine with this as a business model: if we are so used to it, it must be right.
http://www.nejm.org/doi/full/10.1056/NEJMoa1104318

1010 Ingenol mebutate is a really neat treatment for actinic keratosis: four RCTs show that it works with 2-3 applications. It's made from the sap of Euphorbia peplus, the petty spurge which is abundant in many parts of north America. It is doubtless very cheap for Leo pharmaceuticals to produce, and with such a tiny quantity needed for such a brief duration of treatment, perhaps they are thinking of giving the stuff away. Well, actually, one website quotes $699 for 141gm of 0.015% ingenol gel. But don't be tempted to save money and find some petty spurge to put on your keratoses: the sap can burn quite badly.
http://www.nejm.org/doi/full/10.1056/NEJMoa1111170

Lancet 17 Mar 2012 Vol 379

1005 The National Patient Agency has surveyed mental health services in the UK from 1997-2006 to see if there is a relationship between suicide rates and implementation of recommendations to prevent suicide issued by the National Confidential Inquiry. These recommendations include such things as the formation of 24 hour crisis teams and assertive outreach groups for vulnerable patients who are poor attenders of conventional services. People who have both depression and alcohol problems, and are thus at highest risk for suicide, are no longer supposed to be pushed back and forth between services designed for one or the other problem but never both. By and large, the study finds a correlation between the degree of implementation of the recommendations and a fall in suicides. It isn't the ultimate in scientific rigour, but it makes sense. Like all mental health provision in the NHS, it is a rather bleak minimum.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961712-1/abstract

1045 Since serotonin reuptake inhibitors came on the scene, suicide rates have fallen in most countries. Is this cause and effect? There is no methodology which can possibly answer that question, but at any rate it makes it unlikely that they cause increases in suicidal behaviour at a population level. There was one large study of males in the USA which seemed to show that sertraline reduced suicidal behaviour compared to other antidepressants, or none. You can find this and other bits and pieces of information in this review of major depressive disorder: new clinical, neurobiological, and treatment perspectives. There is a convincing mechanistic biochemical explanation for every drug that works for depression, and for every one that has been tried and failed. All the time, extremely clever people are discovering more about the neurobiology of the depressed brain. This article discusses dozens of new pathways we could tinker with. Whether this would produce any results that are better than chance alone, nobody can tell.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960602-8/abstract

BMJ 17 Mar 2012 Vol 344

I haven't been able to access Latest Print Version on the BMJ website for several days, so I have picked a couple of research papers out of the Last 7 Days section.

There's a general feeling that we don't have enough good drugs for type 2 diabetes, and it's hard to argue otherwise. So we should extend a welcome to any new drug that helps to lower blood sugar, especially if it doesn't cause weight gain or hypoglycaemia, right? I'm ashamed to say that until about three years ago I would have nodded in assent. I may even have prescribed a few patients a dipeptidyl peptidase-4 inhibitor (or gliptin) just to show how up to date I could be. But what I was doing was performing an unwarranted human experiment, since we have no idea whether these drugs do more harm than good in the long term. A drop of one point in HbA1c is rarely worth the risk, especially if you don't know what the risk is. This meta-analysis hedges its bets, as it must. But betting in the dark with the long term future of patients is not a good thing to do, ever.
http://www.bmj.com/content/344/bmj.e1369

But perhaps there is a subgroup of diabetic patients who are particularly likely to benefit from treatment with a gliptin, the drug rep or the paid lecturer might argue. Look, in this trial (he says, handing you the reprint), patients with red hair showed a much bigger drop in blood sugar, and moreover their LDL-cholesterol levels were halved. Here are some nice pens and do help yourself to the delicious sandwiches. With Wondagliptin you may be able to meet all your targets for red-headed diabetics, and we can help train your practice nurse to do it with the aid of daily blood glucose monitoring. Do I exaggerate? Not much, I fear. Anyway, back to subgroup analyses. Don't believe them, especially in industry-funded studies. If you are an EBM nerd, or even if you are not, it is worth looking at this systematic review of the credibility of subgroup claims in randomised controlled trials.
http://www.bmj.com/content/344/bmj.e1553

Arch Intern Med 12 Mar 2012 Vol 172

397 About ten years ago, I advised you to train your larynx to pronounce the word ximelagatran, the name of the first direct thrombin inhibitor which seemed poised to replace warfarin for numerous clinical indications. If you followed my advice, you abraded your vocal cords and twisted your palate to no avail, since the drug was withdrawn in 2006 following reports of hepatotoxicity. Its successor dabigatran is easier to pronounce, works well at a fixed dose, and generally seems harmless to the liver. Boehringer Ingelheim seemed to have a winner on its hands. But alas, a cloud no bigger than a man's hand has appeared on the horizon. Here is a meta-analysis which shows that dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls, and that is not something one likes to hear about a drug designed for long term thromboprophylaxis.
http://archinte.ama-assn.org/cgi/content/abstract/172/5/397

Plant of the Week: Euphorbia amygdaloides var robbiae

Like all members of the spurge family, this one seeps toxic sap, though whether it contains ingenol I have no idea. You could make your fortune by finding out. After all, it is a wood spurge that likes to grow in dark places, so its juices are bound to work for something that is caused by sun damage. Or does it work the other way round? I lack grounding in the science of herbalism.

This handsome plant bears the somewhat dismissive label of "excellent for ground cover". All winter long, you have ignored its handsome rosettes of dark leaf, except perhaps on some magical sunny day when they have shone with a covering of frost. Now, as the ground warms, it is sprouting great flower-shoots of pale fresh green. Soon it will go back to its usual job of growing where nothing else will, and sometimes where you don't want it to. Excellent for ground cover, indeed, and lovely in early spring.


JAMA 7 Mar 2012 Vol 307

915 "Almost 2 and a half million people in the United States die every year, making death the most common health event in the United States" says Mary Tinetti in a Viewpoint piece called The Retreat from Advanced Care Planning. It's a strange and somewhat disturbing choice of words, but then Mary is feeling somewhat disturbed. "In the months after the death panel uproar, family members of 2 patients accused me of being part of a government-backed plan to save money by not offering expensive care to frail older patients." Instead, she wanted to talk about the kind of care that was humane and appropriate in the light of the common health event the patient was facing, i.e. death. So a moronic scare campaign dreamt up by Sarah Palin to undermine Obama's Affordable Care Act has ended with patients and families being unable to discuss appropriate end-of-life care, and one of America's foremost advocates for the elderly admitting that "These experiences left me feeling attacked and frankly reluctant to continue an activity that is the core of my responsibility as a physician." God Bless America.
http://jama.ama-assn.org/content/307/9/915.extract

922 A couple of years ago, The Lancet published a case series by an eminent neurosurgeon from Queen Square reporting his superb results with surgery for epilepsy, with most of his patients cured after many years of fits (mostly temporal lobe) which were resistant to multiple medication. Here we have another bit of evidence that temporal lobe epilepsy surgery works - and again it's not a proper, fully powered randomised controlled trial, but a study that was half-completed due to recruitment problems. These trials may not fit into the highest levels of the EBM hierarchy, but the figures here tell their own story: no complete seizure control in the non-surgical group (23), compared with 11 out of 15 seizure-free two years after surgery. No p-values needed.
http://jama.ama-assn.org/content/307/9/922.abstract

NEJM 8 Mar 2012 Vol 366

883 The original title of the most famous text in biology was On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. The one thing that Charles Darwin could not explain in 1859 was how "favoured races" came to acquire their favourable characteristics. He could draw up a phylogenetic tree showing branching evolution,but until the coming of Mendelian genetics and the unravelling of the structure of DNA, nobody could explain exactly how this could operate through the processes of sexual reproduction. In fact it is much easier to observe at the level of asexual reproduction, in single-celled organisms like bacteria - or cancer cells. This ground-breaking British study traces the evolution of renal carcinomas using DNA analysis from the primary tumour site and various metastases. And what emerges is - you nearly guessed it - a phylogenetic tree showing branching evolution for each tumour line, as tumour DNA changes through furious cycles of unregulated division. This in turn means that any single tumour sample will not necessarily reflect the DNA of the cancer as a whole. The ideal of genomic analysis leading to personalized cancer cures gets a reality check when faced with this awesome demonstration of complex adaptive biology at work. Magic bullets will need to hit multiple targets at once: as these brilliant investigators drily remark, cancer heterogeneity "may present major challenges to personalized-medicine and biomarker development".
http://www.nejm.org/doi/full/10.1056/NEJMoa1113205

893 And now for some more good British science supported by the MRC: The Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO) study. This was a multicentre, double-blind, placebo-controlled, clinical trial with a two-by-two factorial design. Most of us have long suspected that these drugs have no clinically meaningful effect on progression in Alzheimer's disease and are largely a waste of money. Well, this trial proves us wrong. Even in patients as far gone as this, with Mini-Mental State scores between 5 and 13, both donepezil and memantine definitely slowed progression when continued, though combining the two had no additional effect. This study and the one before make it a great week for the UK Medical Research Council: glasses of best English sparkling wine should be raised throughout its premises.
http://www.nejm.org/doi/full/10.1056/NEJMoa1106668

925 Ever heard of the word abscopal? It sounds like some obscure ecclesiastical usage - a bishop performs abscopal ordinations outside his diocese, perhaps. Well, in oncology, it refers to the effect of a treatment at one site on metastases elsewhere. Specifically, we are told, "The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system." Neat, and useful. This paper describes the case of a young woman with metastatic melanoma who received treatment with ipilimumab. This wasn't achieving much until she had radiotherapy to a paraspinal mass. Thereupon all her other metastases started shrinking. Four years from the first discovery of metastatic disease, she remains stable on ipilimumab. Let us hope that abscopy proves to be a useful new direction in cancer treatment.
http://www.nejm.org/doi/full/10.1056/NEJMoa1112824

932 Which muscular organ is constantly active from birth to death, sustaining life without our commonly being aware of it? The QI hooter will go off if you answer the heart, although you will be technically correct, of course. But the structure I am referring to here is actually the diaphragm. There is never a week in these medical journals where heart disease is not mentioned, but I think this is the first article I have ever encountered on dysfunction of the diaphragm. We really do take our vital bellows for granted. The fact that we can is testimony to the diaphragm's stolid efficiency in most conditions - except those rather rare and extreme ones described in this article, which I mainly mention for its value as a rarity. (Someone should write an Ode to the Diaphragm, beginning,

Lo, thus I breathe!
Therefore I am!
Let us extol the Diaphragm!
That with its soft unnoticed thrusts
Sustains our life by vital gusts.
)
http://www.nejm.org/doi/full/10.1056/NEJMra1007236

Lancet 10 Mar 2012 Vol 379

895 "The Lancet, you may have noticed, is a seriously weird journal. One of the things it likes to do is publish the results of cutting-edge human experiments before they have any clear outcomes" I wrote here two weeks ago. This hasn't changed in a fortnight, and in fact it hasn't changed in over a decade. During this time there have been lots of small trials of stem cells for repairing myocardium: these were novel and exciting to begin with, but you might be forgiven for wanting some evidence of actual benefit by now. Here in the latest phase 1 trial, CADUCEUS, the stem cells were cardiosphere-derived, i.e. grown from the patients' own cardiomyocytes obtained by endocardial muscle biopsy. Cultured autologous precursor cells were introduced by coronary artery infusion, and at six months there was MRI evidence of scar repair and new myocardium but no change in functional indices at all. There will now be a phase 2 trial. Can't wait. You may want to read more about what hasn't yet happened in this field in the review article (p.933), Towards regenerative therapy for cardiac disease.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960195-0/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960075-0/abstract

905 In the days when I was still a proper doctor with a consulting room of my own, I used to shock and confuse visiting health professionals by keeping a mercury sphygmomanometer with an adult cuff that covered 80% of the upper arm. That way I could at least believe my own blood pressure readings. I even tried to keep abreast of the hypertension literature for a while, since it seemed best to know something about the commonest reason for treating healthy people in primary care. And I even uncovered the odd case of primary hyperaldosteronism. But I very rarely measured the BP in both arms, except in one memorable lady with a cold hand and a loud subclavian murmur, who provided my one and only diagnosis of subclavian stenosis. Here is a frustrating systematic review of the difference in BP between arms and vascular disease and mortality - frustrating because it doesn't place its findings in any useful context. In particular there is a digression about the ankle/brachial pressure index without a direct comparison with the arm/arm BP index, but without clarifying which is more useful in which clinical situations. The authors are willing to commit no further than some mights and coulds: "A difference in SBP of 10 mm Hg or more, or of 15 mm Hg or more, between arms might help to identify patients who need further vascular assessment. A difference of 15 mm Hg or more could be a useful indicator of risk of vascular disease and death."
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961710-8/abstract

BMJ 10 Mar 2012 Vol 344

The latest and best meta-analysis of randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes uses individual patient data to show once again that use of this expensive technology does not lead to any clinically meaningful improvement in glycaemic control. It's high time that guidelines such as NICE reflected this. We encouraged this practice once, in the belief that it would help patients manage their condition better. Then it became a lucrative scam for the test strip manufacturers who could change their systems every few years to ratchet up costs which are borne by the NHS. Now it's time for a reality check, and for some serious questions about futile spending to be addressed.
http://www.bmj.com/content/344/bmj.e486

I'm not a great fan of modelling and simulation and cost-effectiveness studies, though these seem very popular with the BMJ. I like things that I can understand and interrogate. Still, I was rather intrigued by the notion of a Dutch microsimulation model. Does it contain little dykes and windmills and adjust for cannabis use? Prosaically, it is merely based on Dutch cervical screening data, and it reaches a conclusion that I have been wanting to hear from some time - most European countries should consider switching from primary cytology to HPV screening for cervical cancer. But still, Nullius in Verba - the Royal Society motto which roughly means "don't take their word for it". Anything which requires specialist software, Dutch or otherwise, can only be taken on trust.
http://www.bmj.com/content/344/bmj.e670

In 1991, my practice took on a brilliant new partner who was a paediatrician with a special interest in asthma. I can remember saying to him at interview, "Oh good, we need you to sort out the mess which is childhood asthma." In those days, not only did every child who had ever wheezed get the asthma label for life, but also every child who coughed for more than a month, especially at night. Nowadays we distinguish - as we easily could then, if only we had been given official permission to - between pre-school wheezing, post-infective wheezing, atopic asthma, post-infective cough and chronic cough in children. Here at last is a practical review of the last topic which plainly states that "Isolated cough without wheeze or breathlessness is rarely caused by asthma". Some time ago, our practice took part in a study by Anthony Harnden which showed that up to 25% of persistent cough in children and adults is associated with evidence of recent pertussis infection, but most people still seem to be unaware of this. There is nothing to be done but wait it out, anyway. For other diagnostic possibilities, and sensible management advice, keep this article.
http://www.bmj.com/content/344/bmj.e1177

Ann Intern Med 6 Mar 2012 Vol 156

329 A simple and outstandingly useful Dutch RCT demonstrates clearly that early treatment of rheumatoid arthritis with methotrexate and prednisone 10mg daily is superior to methotrexate alone. The primary end-point was erosive joint damage at 2 years. But combination treatment was also superior for minimizing the need for DMARD and biological drugs, and caused fewer adverse effects.
http://www.annals.org/content/156/5/329.abstract

340 Lisa Schwartz and Steve Woloshin have tirelessly striven for over a decade to help people understand how to interpret basic medical numbers and concepts. Some of their effort has been directed at patients, some at the general public, some specifically at journalists, and some at doctors. In this classic study they and two colleagues look at how well American primary care doctors understand cancer screening statistics. The news is worse than you could have believed. "When presented with irrelevant evidence, 69% of physicians recommended the test, compared with 23% when presented with relevant evidence (P < 0.001). When asked general knowledge questions about screening statistics, many physicians did not distinguish between irrelevant and relevant screening evidence; 76% versus 81%, respectively, stated that each of these statistics proves that screening saves lives (P = 0.39)." Aargh.
http://www.annals.org/content/156/5/340.abstract

360 The previous study is not by any means the only one to show that doctors can be very poor at handling numerical data; there have been lots of studies in patients too, and some in surrogate decision makers. Here is a mixed-methods (hurray!) study of how relatives and decision-making carers of people incapacitated by serious disease interpret prognostic information, whether given as numbers or words. Such discussions usually take place in the context of continuing life-supporting treatment, so this could hardly be less trivial. And the investigators find that misunderstanding is rife - and tends to be in one direction only, so that it is not simply misunderstanding but cognitive bias towards optimistic interpretation.
http://www.annals.org/content/156/5/360.abstract

Plant of the Week: Helleborus x ericsmithii

As the growing season begins to unfold its delights, the plants I most look forward to are the hellebores. Alas, I have found none so far in New Haven, perhaps because the soil is lime-free and unfavourable to the whole genus. Or perhaps it has been too cold so far. Back in England, our garden must be awash with self-sown oriental hellebores with their perfect flowers of white, black, pink and yellow, spotted or otherwise - or intriguing dull green, as in the amusing cultivar "Old Ugly".

We also miss the chance to buy new hellebores, which must be done while they are in flower, and from a specialist nursery with a decent choice. I would like at least to see the one named for the greatest of hellebore fanciers gone by, Eric Smith. It has leaves of veined pewter with long flower-stems bearing white flowers with a hint of pink. I think if I saw it I would buy it. I might have already. That's the nice thing about old age, as Ronald Reagan remarked.


NEJM 1 Mar 2012 Vol 366

777 There is no JAMA this week, and the best things in the New England Journal come right at the start. Whether you are a British GP contemplating another set of humiliating idiotic directives and the imminent destruction of the NHS, or an American physician wondering how your crazy health system can ever be turned into something rational and sustainable, or an academic wondering how much more futile research you have to grind your way through and pretend to be interested in, here is the boost you need. Goal-Oriented Patient Care - An Alternative Health Outcomes Paradigm. For the battle-weary GP, an affirmation of the central value of what you came into medicine to do - to help patients to achieve goals that they choose for themselves, in a continuing dialogue about the possible and the practical. For the American system, a model of care that puts the patient at the centre and emphasizes joined-up, affordable care. For the academic, a new research agenda based on what will best inform shared decision-making with patients and society. Download this article by David Reuben and Mary Tinetti at once and keep it under your pillow.
http://www.nejm.org/doi/full/10.1056/NEJMp1113631

The NEJM lets you have this free, and also the companion pieces which follow - about shared decision-making and defining patient-centred care. Both good, but the Reuben/Tinetti is a gem.
http://www.nejm.org/doi/full/10.1056/NEJMp1109283
http://www.nejm.org/doi/full/10.1056/NEJMp1200070

787 Now back to the bizarre world of the medical-industrial complex and the way that it generates "evidence", and large amounts of money, with the help of medical journals. Ruxolitinib is an inhibitor of Janus kinase (JAK) 1 and 2, and it costs about $85,000 for a year's treatment. Here are two new trials of ruxolitinib in myelofibrosis, showing some symptomatic benefit, but no survival benefit compared with best available therapy. Myelofibrosis can't be a particularly rare condition, since I have encountered it several times among the elderly patients of the little flock I once used to shepherd. Once you have it, you will probably die as a result: which is a pity, but then we all have to die of something in old age. So symptomatic benefit is a laudable goal. But how do you go about setting that against costs of this order? The editorial explains a bit more about the issues at stake, but points out that these studies add little to what an NEJM long-term study had shown a few months ago. It concludes: "Approximately 30% of patients with myelofibrosis present with ruxolitinib-sensitive symptoms, and the drug might be useful in a fraction of these patients who are not candidates for allogeneic stem-cell therapy or for clinical trials of potentially better drugs, including newer and more selective JAK inhibitors." So what are these papers doing taking up prime-time space in the world's leading medical journal?
http://www.nejm.org/doi/full/10.1056/NEJMoa1110556
http://www.nejm.org/doi/full/10.1056/NEJMoa1110557

808 Here's a UK trial of nicotine replacement patches to reduce smoking in pregnancy. If this were a pharma-funded trial hoping to sell nicotine patches, we might expect it to have been conducted in 76 centres in 15 countries, but instead this government-funded study recruited from 7 antenatal clinics in the West Midlands, and still managed to be 4 times larger than any previous trial. Unfortunately, though, it showed the same result as all the others: that nicotine replacement in pregnancy has no effect on overall cessation rates.
http://www.nejm.org/doi/full/10.1056/NEJMoa1109582

Lancet 3 Mar 2012 Vol 379

815 The Lancet is back on one of its frequent excursions into China: small recompense from our clapped-out little island which once tried to destroy Chinese civilization by forcing its population to become opium-dependent and then strangling its trade. Alas, the imperialism of bad ideas continues. Western notions of chronic kidney disease have now bestowed silent ill-health on 120 million Chinese people, whose creatinine clearance is dangerously below 60mL/min per 1.73m2, or who have albumin in a single sample. What is to be done? Absolutely nothing, of course. The Chinese health system has far better things to concern itself with, as the preceding article on health coverage and catastrophic expenditure makes clear.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960033-6/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960278-5/abstract

823 Another bad Western idea is that adverse prognostic markers are somehow valuable. If you happen to have had surgery for non-squamous, non-small-cell lung cancer, you can now undergo a practical molecular assay to predict survival, thanks to the efforts of a Chinese team. When pressed, researchers who uncover these harbingers of doom generally claim that they identify a subgroup of patients who deserve special further investigation, or closer clinical follow-up. But in fact all that this test will tell you is whether are likely to snuff it, which is rarely a comforting or useful thing to know.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961941-7/abstract

833 "The pace of reform should be moderated to allow service providers to develop absorptive capacity. Independent, outcome-based monitoring and evaluation by a third-party are essential for mid-course correction of the plans and to make officials and providers accountable." This is the conclusion of an examination of China's huge and complex health care reforms. I suggest that we should send Andrew Lansley and David Cameron on a fact-finding mission to China. Three years should do it.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961880-1/abstract

BMJ 3 Mar 2012 Vol 344

Here's a fact we would rather not face: we cannot really know the safety of devices or drugs over long periods of time unless we test them over similar periods of time. It is certainly not a fact that drugs and devices manufacturers want to face, and more worryingly it is something that regulatory agencies are very poor at addressing on our behalf (see the account of European and US device regulation in NEJM). The bar for introducing new devices is set very low, and once the device is over the bar, post-marketing surveillance is often nugatory. If you think this doesn't concern you, then you must be somebody who has never referred a patient for hip replacement. Metal-on-metal hip prostheses have become hugely popular in the last two decades, and metal resurfacing of the hip is a great British invention in the best Barnes Wallis tradition, perfected by an orthopaedic surgeon rolling his sleeves up and tinkering with cobalt and chromium in his garden shed. Deb Cohen's piece tells it all. So do we really want to face the fact that these devices spread metal ions and particulate matter all over the body, with some obvious harms and others we do not know? Should we insist on a 15-year testing period for all permanent implantable devices? Or should we ignore such uncomfortable facts, and just carry on with a system which supports the great medical devices industry and harms patients?
http://www.bmj.com/content/344/bmj.e1349
http://www.bmj.com/content/342/bmj.d2905

Acute cannabis consumption and motor vehicle collision risk. A meta-analysis, pointing out that you should not drive if you are stoned, just in case you kill somebody.
http://www.bmj.com/highwire/filestream/566209/field_highwire_article_pdf/0.pdf

It was nice of the BMJ to publish this paper led by two physiotherapy PhD students from Sweden, but it would have been better to wait until they had some useful data. It was a 12-week study examining subacromial impingement syndrome. The right kind of exercise helps to avoid surgery during this time period. Aha. And then?
http://www.bmj.com/content/344/bmj.e787

"Profiles for psychological, vasomotor, and sexual discomfort symptoms relative to age at menopause could help health professionals to tailor their advice for women with natural menopause" claim the authors of this study. I'm not entirely sure what the advice might be. Generally it is better to move up social classes as much as possible, and also to get a degree, but only if you do this in your 20s rather than your 50s. Don't marry if you want to avoid late menopausal symptoms. But nobody has done a randomised controlled trial of divorce for symptom control (blinding would be only one of many problems). In all, the main value of this study is to characterize a number of discrete patterns in menopausal symptoms, rather than identify any modifiable factors.
http://www.bmj.com/content/344/bmj.e402

The Uncertainties Page this week has a nice account of the evidence around the use of probiotics to prevent antibiotic-associated diarrhoea. If your patient has ever had diarrhoea associated with antibiotics before, probiotics are certainly worth advising. It may be going too far to recommend their routine use by all healthy individuals taking antibiotics, but then Greek yoghourt is nice to eat anyway.
http://www.bmj.com/content/344/bmj.e682

Arch Intern Med 27 Feb 2012 Vol 172

312 Doctors and patients love to share simple mechanistic explanations of diseases and cures. Angina pectoris is caused by blocked pipes: unblock the pipes, preferably leaving behind something to keep them open, and you have cured the problem; whereas if you just keep on pushing tablets, you're just treating the symptoms without dealing with the cause. Most of us shared this belief with cardiologists and with patients, until the COURAGE trial came along in 2007 to prove otherwise (and the trial was nearly never done because many interventional cardiologists considered it unethical). This meta-analysis looks at this and 7 other trials and confirms the counter-intuitive conclusion that "Initial stent implantation for stable CAD shows no evidence of benefit compared with initial medical therapy for prevention of death, nonfatal MI, unplanned revascularization, or angina." Collusion in mechanistic certainty is one of the great barriers to progress in medicine, and it may cause direct harm to patients, as the next paper illustrates.
http://archinte.ama-assn.org/cgi/content/abstract/172/4/312

There isn't much else of note in this week's printed Archives, but hidden in the Online First section awaiting paper publication is a remarkable study of patient satisfaction in relation to outcomes. This is worth spending some time on. In the USA, the highest quartile of patient satisfaction is associated with 9% higher inpatient care and drug costs, and - wait for it - 26% higher mortality. What is killing America's most satisfied patients? Is there some hidden confounding here (as the editorial hints)? The authors adjust for everything obvious, such as age and health status; so perhaps the kind of medicine these patients are getting really is 26% more dangerous. But this exceeds even the most pessimistic predictions of those of us who have long held that the overprovision that American patients are programmed to demand might be dangerous. Costly, futile, yes: but as lethal as this? I intend to spend an hour with my brilliant group of young overseas doctors at Yale picking over this paper. If nothing else, it will have some lessons on what to avoid in their own health systems. I firmly believe that all health provision should be judged by the experience of patients, but the simple criterion of fulfilled expectation is clearly inadequate, and may be positively dangerous in societies which ratchet up demand for medical services while ignoring costs and harms.
http://archinte.ama-assn.org/cgi/content/abstract/archinternmed.2011.1662

The same set of Online First papers includes a Research Letter from the UK which is relatively reassuring about the value of patient opinion, at any rate about hospital in-patient episodes. British patients have been encouraged to rate their experiences of all 166 acute NHS hospitals on the NHS Choices website. When compared with routinely gathered measures of clinical outcome and hospital-acquired infection, patient opinion showed a high degree of correlation with quality.
http://archinte.ama-assn.org/cgi/content/full/archinternmed.2011.1675

Plant of the Week: Hamamellis mollis

We can't grow witch-hazels on the limy clay of our garden at home, but here in New Haven they thrive on the local acid sand. Many of the colleges have planted them in borders by the road, and they don't seem to mind fairly high levels of motor exhaust. Passers-by in late winter are hit by a sudden wall of spicy scent, and become aware that these medium sized shrubs are covered in thin tassel-heads of dark yellow or (in other species) dull red. Older, larger specimens make a fine sight beneath the blue skies we sometimes enjoy here.

Hamamellis mollis is really a small tree, so you might do better to look for H japonica or the hybrid of the two, called H x intermedia, which comes in colours ranging from pale straw to dark brick. The yellow ones tend to have the most scent. Also, if you happen to have bleeding piles that require immediate attention, you can rush out and use the bark or leaves as an astringent.


 

 

 

 

 

 

 

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Page last edited: 10 April 2012